Vitamin a synthesis and intermediates therefor



Patented Apr. 27, 1954 UNITED STATES PATENT OFFICE Rochester, N. Y., assignors to Eastman Kodak CDmDanY,; Roohester, N. Y., a corporation of New Jersey No Drawing: Application'september 11,1951; Serial N0. 246,167

13 Claims. (01. 260-611) This inventionrelates' to methods of synthesizing vitamin A and to newanaesem intermediates obtained. in the synthesis: o

The successful synthesis of" vitamin A in sufficient yield for commercial production depends upon the selection out of the myriad possible reactions and reactants of --a combination of reaction steps using particular reactants which will combin to producevitamin A as aproduct and produce it in sufficiently highyie'l-d to be economically feasible. Since the biological activity" of vitamin A active material depends upon aspecific molecular structure, it isnecessarythat the synthesis yield a specific basic compound and not an isomer of the compound or a substituted-structure similar to vitamin A. The successful s nthesis of vitamin A is further complicated by the inherent instability of'the complex polyenes of the vitamin A series and their tendency to isomerize, decompose or undergo undesirable side reactions. In many cases} merely a change in the order in which a particular combination of reactions is carried out will defeat the successful synthesis 'of'vitamin AI I V I It is accordingly an obje'ctbf this invention to provide a new and hi'ghly'effmtive method of synthesizing vitamin A. I

Another object of the invention isto'provide' a new combination of n'iethodsteps which combine' to produce the desired vitamin'A -molei'n'ilar structure. I

Another object of' the invention 'is'to provide an improved method of minimizingobjectionable effects of decomposition; isomerizat'ion; andfside reactions normally attendant to vitammns 'ntheses.

Another object of the inventioifis' to provide a new method of eifectivelyj converting easons to vitamin'A alcohol in good yield.

Another object of the "invention is to'provide a new synthesis of vitamin A involving dehydration of hydroxy pol'yenesbut whichefiectively minimizes yield'losses nqrm'auy" encounteredduring dehydration due to isomerization.

Another object of the invention is to synthesize vitamin A through hitherto unknown intermediates.

Another object of the invention is to provide new and useful vitamin A intermediates.

Another object of the inventioriis to"co nvert e-ionone to vitamin A alcohol through vitamin A aldehyde.

Other objects will be apparent from the description and claims which follow.

These and other objects of the invention are attained by the process'emb'odying this invention and comprising reacting an acetal of a-cetoacetaldehyde with a propinyl halide toform a carbinol, condensing the carbinol Withp-ionone to form an acetylenic diol, hydrogenating the acetylenic' diol to the corresponding clefinic diolfand converting the olefinic diol to vitamin' A aldehyde which in turn" can'be reduced to vitamin A alcohol, the converting of the olefinic diol including dehydration, hydrolysis and treatment with a basic material either sequentially or simul taneously as described more fully hereinafter. The dehydration, hydrolysis,rearrangement and reduction which comprise theconversion of the olefinic diol to'vitamin A alcohol canbe effected in a succession of separate steps or in combinations of steps as described more fully hereinafter. Vitamin A alcohol as prepared by processes embodyingthe invention can, of course, be esterified by well-known esterification procedures to produce vitamin A esters such as the acetate or palmitate or similar esters"; vitamin A usually being sold commercially in th'e form of esters. r 7

The "invention is illustrated bythe following reactions and equations. The equations are set out asseparat'e steps for illustrative-purposes but it will be'understood that one or more of the individual reactions can proceed-in a single reaction mixture without isolation of} the inter mediates, although the intermediate canbe isolated and the "various steps carried outin succession if desired. Various mechanisms may be advancedto explain the observed results without changing the operative steps set out.

As an initial step in the processes embodying the invention, an acetal of acetoacetaldehyde is condensed with a propinyl halide such as propargyl bromide, propargyl chloride or propargyl iodide toform the ca'rbinol; 1, l-dialkoxy3- methyl-3-hydroxy-hex-5-yne. The condensation is effected by use of either zinc or magnesium; the use of magnesium being preferred. Particularly eiiicacious' results are obtained when the magnesium; is catalyzed by mercury, added either as elemental mercury or as a mercury compound such as mercuric chloride or similar mercury salt or as a preferred amalgam With magnesium." There'actionproduct is hydrolyzed to decompose the metallic-organic complex to'the carbinol The acetal is preferably a dialkyl acetal although the exact nature of the acetal grouping does not affect the course of the reaction. Thus any acetal ofacetoacetaldehyde can be employed. the loweralkoxy compounds such asthe dimethoxy, diethoxy," diprop'oxyand dibutoxy acetals being preferredforconvenience. The reaction of thepropinyl halide and the metal of acetoacetaldehyde is'illustrated by the following 3 equation wherein X is a halogen atom and R is an alkyl group:

CH3 CHEC-CHz( JCHz CH(OR)2 Compound I Equation I The carbinol, Compound I, is then condensed with fl-ionone by a Grignard type reaction preferably employing an alkyl magnesium halide in accordance with known chemical practices, such Grignard compounds as ethyl magnesium bromide, methyl magnesium bromide and the like being eminently suitable. The condensation whereby an acetylenic diol, 1,1-dialkoxy-3fl-dimethyl 3,7 dihydroxy 9 (2,6,6 trimethylcyclohex-l-enyl) -nona-8-ene-5-yne, is formed is illustrated by the following equation wherein R is an alkyl group and X is a halogen atom.

HaC CH3 CH=CHC=O RMgX Compound I -CHa H3O CH3 CH3 CH3 CH=CH-(|3CECCH2-CCH2CH(OR)i OH OH CH3 Compound II Equation II The acetylenic diol, Compound II, is thereafter hydrogenated to the corresponding olefinic diol, 1,1 dialkoxy 3,7 dimethyl 3,7 dihydro-Xy- 9 (2,6,6 trimethyl cyclohex 1 enyl) nona- 5,8 diene, by partially hydrogenating the acetylenic linkage. The partial hydrogenation is readily effected by reacting substantially one molecular equivalent of hydrogen With Compound II in the presence of a hydrogenation catalyst such as palladium, Raney nickel or similar well-known hydrogenation catalyst in accordance with usual hydrogenation practices. The reaction is illustrated graphically as follows, R being an alkyl radical:

Compound II H2 Catalyst Compound III Equation III The olefinic diol, Compound III, is thereafter converted to vitamin A alcohol by dehydration, hydrolysis, rearrangement and reduction. In a preferred embodiment, Compound III is treated with a dehydrating agent which is either a halide or an oxyhalide to dehydrate and convert Compound III to the enol ether, 1-alko-xy-3,7dimethyl 9 (2,6,6 trimethyl cyclohex 2 ene- 1-ylidene)-nona-l,3,5,7-tetraene. The reaction is effected by treating Compound III, in solution in a suitable solvent such as benzene, toluene, ether or the like, with a halide or oxyhalide dehydrating agent, and desirably in the presence of a tertiary amine such as pyridine, lutidine or the like. Any of the well-known halide or oxyhalide dehydrating agents can be employed, typical dehydratin agents which are suitably employed including phosphorous oxychloride, benzene phosphorous oxydichloride, boron trifiuoride, aluminum chloride, phosphorous pentachloride, stannic chloride and the like. Treatment with such dehydrating agents usually effects conversion of the acetal group to an ether group simultaneously with the dehydration. The following equation illustrates the reaction:

Dehydrating agent 0 ompound Hi Tert. Amine Ha C C H3 CH2 CH3 C Ha Compound IV Equation IV The enol ether, Compound IV, is readily hydrolyzed to Compound V for which the structure set out in Equation V has been postulated by treatment with an ionizable acid in accordance with well-known hydrolysis practice, a mineral acid such as hydrochloric, phosphoric, sulfuric or the like in solvent media such as acetone, methyl ethyl ketone or the like being desirably employed, although dilute aqueous acid can be employed or such well-known acids as acetic acid or the like. Equation V is illustrative of the reaction:

Compound IV H3O CH3 CH3 OH:

CHs

Compound V Equation V Compound V is rearranged by treatment with a basic catalyst such as a basic amine, an alkaline soap, an alkaline hydroxide, an alkaline adsorbent, an alkali metal alkoxide, a quaternary ammonium base, a basic anion exchange resin, a basic salt, or similar material of basic character. Typical materials of basic character suitable for catalyzing the rearrangement include pyridine, sodium hydride, sodium hydroxide, potassium hydroxide, sodium aluminum silicate, aluminum isopropoxide, potassium acetate, lutidine, lithium aluminum hydride and other well-known basic materials. The rearrangement proceeds either at room temperature or at elevated temperatures with only a catalytic amount of basic material being necessary although larger amounts are not objectionable. By use of a basic adsorbent such as sodium aluminum silicate, the Compound V is purified and rearranged simultaneously. Basic reducing agents such as the ether-soluble basic metal hydrides and aluminum alkoxides cause rearrangement and reduction in a single reaction mixture as described more fully hereinafter. The rearrangement is illustrated in the following equation:

Basic Compound V Catalyst me on,

\/ CH3 CE:

Vitamin A aldehyde Equation VI Vitamin A aldehyde isreadily reduced to" vitamin. A alcohol by treatment with an ether-soluble metal hydride such as sodium aluminum hydride, lithium aluminum hydride; lithium borohydride. or the like; bytreatment with an aluminum alkoxide such as aluminum isopropoxide, aluminum tert.-butoxide or the like with the cor"- responding or other suitable mon'ohydric alcohol; or by other well-known method of reducing 01efim'c aldehydes to olefini'c alcohols". The. reduction is effected in accordance with usual reduction practices. Inthe caseoflthebasic reducing agents, the aldehyde, Compound V, is. desirably treated directly with the reducing agent whereby the basic reducing agent catalyzes the rearrangement to vitamin A- aldehyde and reduction to vitamin A alcohol in a single reaction mixture.

The conversion of theolefinic diol, Compound III, to vitamin A alcohol by dehydration, hydrolysis, rearrangement and reduction. is desirably effected in a preferred embodiment by treating Compound III with a. mixture of an. ionizable acid, preferably a mineral acid, and an organic base such as pyridine, lutidine, quinoline, morpholine, piperidine or the like; or by treating it with an acid-organic base addition product such as pyridine hydrochloride, quinoline hydrobromide or the like;, whereby Compound III is dehydrated, hydrolyzed and rearranged to vitamin A aldehyde in a single reaction mixture, the vitamin A aldehyde then being reduced to vitamin A alcohol as described hereinabove.

The invention is illustrated by the following examples of preferred embodiments. The ultraviolet absorption data (Evalues) in the following examples were determinedin ethanol in accordance with usual. practice.

Example 1 A mixture of 26.2 g. of iodine-activated. zinc dust and 0.07 g. of copper acetoacetate was placed in a flask. To this mixture was added one third of a solution: of 26.5 g. of the dimethoxy acetal of acetoacetaldehyde, 26.2 g. of propargyl bromide and 0.15 g. of hydroquinone in 200 ml. of absolute etherv and-ml. of benzene, andthe resulting mixture was warmed for about 10. minutes to initiate the-reaction. Ifhe remainder of the solution was then added dropwise over a 30 minute period, the reaction mixture. being refluxed and stirred during the addition. When the addition was completed, refluxing was continued for an additional 30. minutes. The metallo-organic complex was decomposed by the addition of saturated ammonium chloride solution, and the mixture was extracted with ether. The ether extract was dried. over anhydrous sodium sulfate, and the solvent removed by evaporation to give 55-60 ml. ofcrude product. This product was fractionated under vacuum to give 20.04 g. of Compound I: having a boiling point of 87-92" C. at 12 mm. Hg. Infrared analysis confirmed the presence of the triple bond and the hydroxyl group.

Example 2 The reaction mixture was warmed for 6. which time the reaction proceeded vigorously without heating for 30= minutes while controlled by cooling in an ice-water bath. Themixture was then heated to reflux for an additional 30 minutes and was stirredduring such additional reflux. A 5% solution ofaqueous sulfuric acid was added cautiously todecompose the magne sium complex. The ether phase was separated from the aqueous phase, and the aqueous phase extracted with additional ether. The ether extracts were combined, washed with saturated sodium bicarbonate solution and dried over anhydrous-sodium sulfate. The ether was removed by evaporation togive 7.88 g. of crude Compound I which was thereafter fractionated under vacuum to give 3.76 g. of 'CompoundI having a boiling point of 60 C. atBmm. Hg.

Example. 3--

A 161-ml. portion of an ethereal solution of ethyl magnesium bromide prepared from 14.6 g. of magnesium foil, 65.5 g. of ethyl bromide and 210 ml. of absolute ether was transferred under nitrogen to a 3-necked flask equipped with a reflux condenser, astirrer and a dropping funnel. To this solution was slowly added 32.99 g. of Compound I (B. P. 68.5-72 at 4 mm. Hg n 1.4512) dissolved in '75 m1. of absolute ether, the addition being dropwise over a 20 minute. period. The resulting mixture was refluxed gently overnight, and then 48.5 g. of fi-ionone dissolved in 75 ml. of absolute ether was added at room temperature. The resulting reaction mixture was stirred for 2 hours, with refluxing during the final 30 minutes. The magnesium complex was decomposed with ammonium chloride solution, and the product worked up by separating the ether phase from the aqueous phase, extracting the aqueous phase with. additional ether, combining the ether extracts, drying the ether extract and removing'the other by evaporation. The crude Compound II thus obtainedweighed 68.9 g. and had Elf}... (308 m :332v

and

E1? (232' mp) =220 After purification by chromatography, the acetylenic diol, Compound II, was obtained having Ex (232 m =115 Example 4 Four grams of the acetylenic diol, Compound II, were dissolved in 40 ml. of methyl alcohol containing 3 drops of quinoline and 0.55g. of 5% palladium-charcoal. Hydrogen was passed into the solution and 367 ml; (1 molecular equivalent) of hydrogen was adsorbed in 15 minutes. The hydrogenation was continued for an additional 10 minutes during which time 18 ml; of additional hydrogen was absorbed for a total amount of 1.05molecular equivalents of hydrogen. The reaction mixturewas then diluted with ml. of petroleum ether and filtered to remove the catalyst. The ether phase was washed with 5% sulfuric acid, dilute sodium bicarbonate solu tion and water. After drying over anhydrous sodium sulfate, the solvent was removed by evaporation to give 7.34 g. of the olefinic diol, Compound III, having Elfi (232 my) 187 Example 5 A 1.99-g. portion of phosphorous oxychloride dissolved in 10 ml. of dry toluenewas-slowlyadd-- ed to 6.6 ml. of pyridine, the mixture being cooled during the addition. A solution of 1.83 g. of the oleflnic diol, Compound III, in 50 ml. of dry toluene was then added, and the resulting reaction mixture was heated at 90-95 C. for 75 minutes with rapid stirring. The reaction mixture was then cooled and stirred into 30 g. of crushed ice and ether. The aqueous phase was separated from the ether phase and the aqueous phase extracted with additional ether. The combined ether phases were washed successively with saturated potassium carbonate solution, excess sulfuric acid, and saturated sodium bicarbonate solution. The extract was dried and the solvent removed by evaporation to give 1.1 g. of the enol ether, Compound IV, having Elf... (372 m11 =750 Example 6 A 1.09-g. portion of the enol ether, Compound IV, was dissolved in ml. of acetone containing 2 drops of concentrated hydrochloric acid. The reaction mixture was refluxed for minutes, the acetone removed by evaporation and the residue taken up in ether. The ether solution was washed successively with saturated sodium bicarbonate solution, and water, dried over anhydrous sodium sulfate and the ether removed by evaporation to give 0.95 g. of the Compound V, having El? (328 my) =900 Example 7 Compound V was rearranged to vitamin A a1- dchyde by dissolving 0.83 g. of Compound V in petroleum ether, and passing the solution through a column of synthetic sodium aluminum silicate as basic catalyst. Vitamin A aldehyde weighing 0.58 g. and having was obtained as product.

Example 8 A 1.0 g.-portion of Compound V having Elfi (328 my) =794 was dissolved in 5 cc. of benzene to which was added 10 drops of pyridine. The mixture was allowed to stand overnight at room temperature whereupon Compound V was rearranged to vitamin A aldehyde having E max.=3'l0 m Example 9 A 0.8-g. sample of Compound V was dissolved in 6 cc. of ethanol and 9 drops of 0.5 N potassium hydroxide solution were added to the solution. The resulting mixture was allowed to stand at room temperature for 3 hours, and the product was washed with water and dried over sodium sulfate to give vitamin A aldehyde having Eifg (370 mp.)=527 Example 10 An 0.84-g. portion of vitamin A aldehyde dissolved in ml. of absolute isopropyl alcohol was added to 10 ml. of absolute isopropyl alcohol containing 1.85 g, of aluminum isopropoxide. The resulting mixture was refluxed at a rate effective to give 10 drops of distillate per minute, additional isopropyl alcohol being added to maintain the volume. After 30 minutes, the distillate no longer gave a positive acetone test with 2,4-dinitrophenyl hydrazine reagent. The reaction mixture was refluxed for an additiona1 30 minutes and most of the excess isopropyl alcohol was removed under slightly reduced pressure. The residue was cooled, hydrolyzed with cold 5% hydrochloric acid, and extracted with ether. The extract was stabilized with a few crystals of hydroquinone, and then washed successively with saturated sodium bicarbonate solution and water. After being dried, the extract was evaporated to remove the solvent giving 0.85 g. of vitamin A alcohol concentrate as a viscous reddish oil having i'ffm. e) 1175 and a potency by blue color test of 2,120,000 units of vitamin A per gram.

Example 11 A preferred embodiment of the invention includes treating Compound V, with a basic reducing agent and rearranging Compound V to vitamin A aldehyde and reducing the vitamin A aldehyde to vitamin A alcohol in a single reaction mixture. In a typical example, 0.63 g. of Compound V dissolved in 6.3 m1. of anhydrous ether was charged into a 40 ml. 3-necked flask equipped with a stirrer, dropping funnel and reflux condenser. To this solution was added as rapidly as possible, 3.8 ml. of a l M ethereal solution or" lithium aluminum hydride diluted with 3.8 ml. of anhydrous ether. The addition was completed over a period of about 30 seconds during which time the reaction mixture refluxed vigorously. After the addition was completed, the mixture was stirred for one minute, and the excess lithium aluminum hydride was then decomposed by the addition of wet acetone. The mixture was extracted with ether and the ether extract was washed successively with sodium bicarbonate solution and water. The extract was dried over anhydrous sodium sulfate and the solvent removed by evaporation to give a concentrate of vitamin A alcohol having E}'?,,, (328 m =566 Example 12 Simultaneous rearrangement and reduction of Compound V was also effected with aluminum alkoxide. To a suspension of 1.35 g. of aluminum isopropoxide in 10 ml. of isopropyl alcohol was added 0.61 g. of Compound V dissolved in 25 ml. of isopropyl alcohol. The resulting reaction mixture was refluxed until the distillate gave a negative acetone test with 2,4-dinitrophenyl hydrazine. The excess alcohol was then distilled off under vacuum, the residue was cooled and the excess aluminum isopropoxide was decomposed by the addition of 20 ml. of 10% sulfuric acid. The mixture was extracted with ether and the ether extract washed to neutrality with water. The ether was removed by evaporation to give a concentrate of vitamin A alcohol having Em, (328 m =690 Emample 13 1500 cc. of water and extracted with ether.

ether extract was washed successively with 5% centrated hydrochloric acid wereadded to :a solution of 11:0 g. of Compound III in .80 cc. of methyl ethyl .ketone. The resulting mixture was refluxed for 90 minutes, cooled, poured into The hydrochloric acid, 0.5 N potassium hydroxide, and water. The washed extract "was then dried and evaporated to give 8.7 g.'0fVitamlI1-A aldehyde-as a-reddish oil having Eii' (372 ma)'='870 Example 14 Example 15 A 1.0-g. portion of Compound III was refluxed in 12 cc. of methyl ethyl 'ketone containing 0.1 g. of piperidine-and 0.117 g. of concentrated hydrochloric acid. After .a '2 hour refluxmrude vitamin A aldehyde having E12 (368 mI.L)'=610 was obtained.

Example 16 A 0.57-g. portion of vitamin A aldehyde was dissolved in ml. of dry ether. To this was added over a 30 sec. interval, 1.06 ml. of a l M ethereal solution of lithium aluminum hydride diluted with 1 ml. of dry-ether. The mixture was stirred for 1 minute following the addition, and excess lithium aluminum hydride was decomposed by the addition of Wetether, acetone andB aqueous hydrochloric acid successively. Th mixture was extracted with ether, the ether extract washed with sodium bicarbonate solution and water, and the extract dried over anhydrous sodium sulfate. After removal of the solvent by evaporation, 0.56 g. of crude vitamin A alcohol was obtained having and a vitamin A potency by blue color assay of 1,520,000 units per gram.

The invention thus provides a new combination of method steps which combine to produce vitamin A while minimizing undesirable yield-reducing effects of isomerization, :side reactions and the like. I

While the invention has been described'in considerable detail with reference to certain preferred embodiments thereof, it will be understood that variations and modifications can be effected therein without departing from the spirit and scope of the invention as described hereinabove and as defined in the appended claims.

We claim:

1. In the synthesis of vitamin A, the method which comprises reacting an acetal of acetoacetaldehyde with a propargyl halide in the presence of a metal selected from the class consisting of zinc and mercury-catalyzed magnesium, con- (lensing the resulting reaction product with B- ionone by means oi magnesium in a Grignard reaction, and partially hydrogenating the acetylenic linkage of the resulting condensation prodnot and thereby "obtaining an olefinic 3,7-diol acetal.

2. The method of synthesizing vitamin A which comprises condensing an acetal of acetoacetaldehyde with a propargyl halide in the presence of mercury-catalyzed magnesium, condensing the resulting reaction product with c-ionone by means of magnesium in a Grignard reaction, subjecting the resulting condensation product to partial hydrogenation effective to reduce the acetylenic linkage of said condensation product to an olefinic linkage by reacting said condensation product with a molecular equivalent of hydrogen in the presence of a hydrogenation catalyst and thereby forming an olefinic 3,7-diol acetal, converting said olefim'c 3,7-diol acetal to vitamin A aldehyde by .dehydrating and hydrolyzing said olefinic 3,7-diol acetal to an isomer of vitamin A aldehyde and rearranging said isomer tovitam-in A aldehyde with a basic catalyst, and reducing said vitamin A aldehyde to vitamin A alcohol.

3, In the synthesis of vitamin A, the steps which comprise condensing a dialkyl acetal of acetoacetaldehyde with a propargyl halide in the'presence of mercury-activated magnesium and thereby forming the carbinol, 1,1-dialkoxy-3-methyl- S-hydroxy hex-5-yne, condensing .said carbinol with fi-ionone in a Grignard reaction with magnesium and thereby forming the acetylenic diol, 1,1 dialkox 3,7 dimethyl 3,7 --dihy.droxy 9 (2,6,6 trimethyl cyclohex 1-- enyl) nonaene-5-yne, and partially hydrogenating said acetylenic diol to the olefinic diol, 1,1-dialkoxy- 3,7 dimethyl 3,7 dihydroxy :9 (2,6,6 trimethyl cyclohex 1 enyl) nona 5,8 diene.

4. The method of making vitamin .A which comprises condensing a dialkyl acetal of acetoacetaldehyde with a propargyl halide in the -pres-- ence of a member of the group consistingof zinc and mercury-activated magnesium and thereby forming the carbinol, 1,1dialkoxy3-methy-l-3 hydroxy .hex-5-yne, condensing said carbinol with fl-ionone by means of magnesium in aGrignard reaction and thereby forming the acetylenic diol, 1,1-dialkoxy-3,7-dimethyl-3,7-dihydroxy-9- (2,6,6 trimethyl cyclohex-l-enyl)--nona-8-ene- 5-yne, partially hydrogenating said .acetylenic diol to the olefinic diol, l,l-dial-koxy3,7-dimethyl 3,7 dihydroxy .9 (2,6,6 trimethyl cyclohex l enyl) nona 5,8 dime, and converting said olefinic diol to vitamin A alcohol, said converting comprising dehydrating said olefinic diol with a member selected from the class consisting of phosphorous halides and phosphorous oxyhalides and thereby -forming the enol other, 1 alkoxy 3,7 dimethyl 9 (2,6,6 tri-methyl cyclohex '2 ene i ylidene) -nona 1,3,5,7 'tetraene, shy- -d-rolyzi-ng said enol ether, :and reacting the product of :said hydrolyzing with a :bas'ic reducing agent and thereby forming yitaminA alcohol.

5. The method of making vitamin A which comprises condensing a dialkyl acetal of acetoacetaldehyde with a propargyl halide in the presence of a member of the group consisting of zinc and mercury-activated magnesium and thereby forming the carbinol, 1,1-dialkoxy-3-methyl- 3-hydroxy hex-5-yne, condensing said carbinol with ,c-ionone by means of a Grignard reaction and thereby forming the acetylenic diol, 1,1-dialkoxy 3,7 dimethyl 3,7 dihydroxy 9 (2,6,6 trimethyl cyclohex 1 enyl) nona 8-ene-5-yne, partially hydrogenating said acetylenic diol to the olefinic diol, l,ldialkoxy-3,7-dimethyl-3,7-dihydroxy-9-(2,6,6-trimethyl cyclohex- -enyl)-nona-5,8-diene, and converting said olefinic diol to vitamin A alcohol, said converting comprising heating said olefinic diol in admixture with an ionizable acid and an organic base and thereby forming vitamin A aldehyde, and reducing said vitamin A aldehyde to vitamin A alcohol.

6. The method of making vitamin A which comprises condensing a dialkyl acetal of acetoacetaldehy-de with a propargyl halide in the presence of a member of the group consisting of zinc and mercury-activated magnesium and thereby forming the carbinol, 1,1-dialkoxy-3-methyl-3- hydroxy heX-S-yne, condensing said carbinol with 6-ion0ne by means of a Grignard reaction and thereby forming the acetylenic diol, 1,1-dialkoxy 3,7 dimethyl 3,7 dihydroxy 9 (2,6,6 trimethyl cyclohex 1 enyl) nona 8 ene yne, partially hydrogenating said acetylenic diol to the olefinic diol, 1,1-dialkoxy- 3,7 dimethyl 3,7 dihydroxy 9 -(2,6,6 trimethyl cyclohex 1 enyl) nona 5,8 diene, and converting said olefinic diol to vitamin A alcohol, said converting comprising dehydrating and hydrolyzing said olefinic diol to the aldehyde, 3,7 dimethyl 9 (2,6,6 trimethyl cyclohex 2 ene l ylidene) nona 2,4,6 triene 1 a1, and treating said aldehyde with a basic reducing agent and thereby rearranging and reducing said aldehyde to vitamin A alcohol.

7. In the synthesis of vitamin A, the method of making an olefinic diol which is convertible to vitamin A alcohol by dehydration, hydrolysis and reduction which comprises condensing a dialkyl acetal of acetoacetaldehyde with propargyl bromide in the presence of mercury-catalyzed magnesium and thereby forming the carbinol, 1,1 dialkoxy 3 methyl 3 hydroxy hex 5 yne, condensing said carbinol with ,B-ionone by means of an alkyl magnesium halide and thereby forming the acetylenic diol, 1,1dialkoXy-3,7-di methyl 3,7 dihydroxy 9 (2,6,6 trimethyl cyclohex 1 enyl) nona 8 ene 5 yne, and partially hydrogenating said acetylenic diol to the olefinic diol, 1,1-dialkoxy-3,7-dimethyl- 3,7 dihydroxy 9 (2,6,6 trimethyl cyclohex- 1 enyl) nona 5,8 cliene.

8. The method of making vitamin A which comprises condensing a dialkyl acetal of acetoacetaldehyde with a propargyl halide in the presence of mercury-catalyzed magnesium and thereby forming the carbinol, 1,1-diallcoxy-3-methyl- 3-hydroxy heX-5-yne, reacting said carbinol with an alkyl magnesium halide and B-ionone and thereby condensing said fi-ionone with said carbinol to form the acetylenic diol, 1,1-dialkoxy- 3,7 dimethyl 3,7 dihydroxy 9 (2,6,6 trimethyl cyclohex l enyl) nona 8 ene 5, yne, subjecting said acetylenic diol to catalytic hydrogenation with one molecular equivalent of hydrogen and thereby partially hydrogenating said acetylenic diol to the olefinic diol, 1,1-dialkoxy 3,7 dimethyl 3,7 dihydroxy 9 (2,6,6 trimethyl cyclohex 1 enyl) nona 5,8-diene, dehydrating and hydrolyzing said olefinic diol to aldehydic material, and reducing said aldehydic material to vitamin A alcohol with a basic reducing agent.

9. The method of making vitamin A which comprises condensing a dialkyl acetal of acetoacetaldehyd with propargyl bromide in the presence of mercury-catalyzed magnesium, reacting the resulting carbinol with an alkyl magnesium halide and ,B-ionone and thereby condensing said B-ionone with said carbinol, subjecting the resulting condensation product to catalytic hydrogenation with one molecular equivalent of hydrogen, heating the product of said hydrogenating with an ionizable acid and an organic base and thereby forming vitamin A aldehyde, and reducing said vitamin A aldehyde to vitamin A alcohol.

10. As a new compound useful in the synthesis of vitamin A, 1,1-dia1koxy-3-methyl-3-hydroxy heX-5-yne.

11. The polyene diol, 1,1-dialkoxy3,7-dimethyl 3,7 dihydroxy 9 (2,6,6 trimethyl cyclohex 1 enyl) nona 8 ene 5 yne.

12. The polyene diol, 1,1dialkoxy-3,7-dimethyl 3,7 dihydroxy 9 (2,6,6 trimethyl cyclohex 1 enyl) nona 5,8 diene.

13. The method which comprises condensing a dialkyl acetal of acetoacetaldehyde with a propargyl halide in the presence of a member of the group consisting of zinc and mercury-activated magnesium and thereby forming the carbinol, 1,1 dialkoxy 3 methyl 3 hydroxy hex 5 yne, condensing said carbinol with B-ionon by means of a Grignard reaction and thereby forming the acetylenic diol, 1,1-dialkoxy-3,7-dimethyl 3,7 dihydroxy 9 (2,6,6 trimethyl oyclohex 1 enyl) nona 8 ene 5 yne, partially hydrogenating said acetylenic diol to the olefinic diol, 1,1-dialkoxy-3,7-dirnethyl-3,7- dihydroxy 9 (2,6,6 trimethyl cyclohex 1 enyl)-nona5,8-diene, and dehydrating and hydrolyzing said olefinic diol.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Heilbron, J Chem. Soc. (England), March 1948, p. 386-393.

Isler, Chimia, vol. 4, May 1950, p. 115.

Prevost et al., Comp, Rend, vol. 1186-1188. 

6. THE METHOD OF MAKING VITAMIN A WHICH COMPRISES CONDENSING A DIALKYL ACETAL OF ACETOACETALDEHYDE WITH A PROPARGYL HALIDE IN THE PRESENCE OF A MEMBER OF THE GROUP CONSISTING OF ZINC AND MERCURY-ACTIVATED MAGNESIUM AND THEREBY FORMING THE CARBINOL, 1,1-DIALKOXY-3-METHYL-3HYDROXY HEX-5-YNE, CONDENSING SAID CARBINOL WITH B-IONONE BY MEANS OF A GRIGNARD REACTION AND THEREBY FORMING THE ACETYLENIC DIOL, 1,1-DIALKOXY -3,7-DIMETHYL-3,7-DIHYDROXY-9(2,6,6-TRIMETHYL CYCLOHEX -1-ENYL)--NONA8-ENE-5-YNE, PARTIALLY HYDROGENATING SAID ACETYLENIX DIOL TO THE OLEFINIC DIOL, 1,1-DIALKOXY3,7-DIMETHYL-3,7-DIHYDROXY-9-(2,6,6-TRIMETHYL CYCLOHEX-1-ENYL)-NONA-5,8-DIENE, AND CONVERTING SAID OLEFINIC DIOL TO VITAMIN A ALCOHOL, SAID CONVERTING COMPRISING DEHYDRATING AND HYDROLYZING SAID OLEFINIC DIOL TO THE ALDEHYDE, 3,7-DIMETHYL-9-(2,6,6-TRIMETHYL CYCLOHEX2-ENE-1-YLIDENE)-NONA-2,4,6-TRIENE-1-AL, AND TREATING SAID ALDEHYDE WITH A BASIC REDUCING AGENT AND THEREBY REARRANGING AND REDUCING SAID ALDEHYDE TO VITAMIN A ALCOHOL. 